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Dopamine D₂-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive 4 nicotinic receptors via a cholinergic-dependent mechanism

Rubing Zhao-Shea^*, Bruce N. Cohen, Herwig Just, Tristan McClure-Begley, Paul Whiteaker, Sharon R. Grady, Outi Salminen^||, Paul D. Gardner^*, Henry A. Lester and Andrew R. Tapper^*,1

^* Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA;

Division of Biology, California Institute of Technology, Pasadena, California, USA;

Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA;

Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA; and

^|| Department of Pharmacy, Division of Pharmacology and Toxicology, University of Helsinki, Helsinki, Finland

¹ Correspondence: University of Massachusetts Medical School, Brudnick Neuropsychiatric Research Institute, 303 Belmont St., Worcester, MA 01604. E-mail: andrew.tapper{at}umassmed.edu

Recent studies suggest that high-affinity neuronal nicotinic acetylcholine receptors (nAChRs) containing 4 and β2 subunits (4β2*) functionally interact with G-protein-coupled dopamine (DA) D₂ receptors in basal ganglia. We hypothesized that if a functional interaction between these receptors exists, then mice expressing an M2 point mutation (Leu9'Ala) rendering 4 nAChRs hypersensitive to ACh may exhibit altered sensitivity to a D₂-receptor agonist. When challenged with the D₂R agonist, quinpirole (0.5–10 mg/kg), Leu9'Ala mice, but not wild-type (WT) littermates, developed severe, reversible motor impairment characterized by rigidity, catalepsy, akinesia, and tremor. While striatal DA tissue content, baseline release, and quinpirole-induced DA depletion did not differ between Leu9'Ala and WT mice, quinpirole dramatically increased activity of cholinergic striatal interneurons only in mutant animals, as measured by increased c-Fos expression in choline acetyltransferase (ChAT)-positive interneurons. Highlighting the importance of the cholinergic system in this mouse model, inhibiting the effects of ACh by blocking muscarinic receptors, or by selectively activating hypersensitive nAChRs with nicotine, rescued motor symptoms. This novel mouse model mimics the imbalance between striatal DA/ACh function associated with severe motor impairment in disorders such as Parkinson’s disease, and the data suggest that a D₂R–4*-nAChR functional interaction regulates cholinergic interneuron activity.—Zhao-Shea, R., Cohen, B. N., Just, H., McClure-Begley, T., Whiteaker, P., Grady, S. R., Salminen, O., Gardner, P. D., Lester, H. A., Tapper, A. R. Dopamine D₂-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive 4 nicotinic receptors via a cholinergic-dependent mechanism.

Key Words: acetylcholine • striatum • nicotine • parkinsonian • interneuron